BACKGROUND The association between cytomegalovirus (CMV) immune globulin (CMVIG) and clinical outcomes in pediatric heart transplantation has not been evaluated. Long-term recipient and graft survival were compared between pediatric heart recipients who received CMV prophylaxis with CMVIG (with or without antivirals), antivirals without CMVIG, and no prophylaxis. CMVIG (with or without antivirals) versus no prophylaxis was also assessed in the CMV-positive donor/CMV-negative recipient cohort. METHODS Data from the Scientific Registry of Transplant Recipients included patients with a transplant date between January 1995 and October 2008; follow-up data were through March 2009. All pediatric (younger than 18 years) recipients of primary, single-organ heart transplants were included. Kaplan-Meier analysis was used to examine rates of recipient death and graft loss at 7 years posttransplantation. Cox proportional hazards regression was used to estimate adjusted risk for graft loss and death. RESULTS CMVIG (with or without antivirals) and antivirals without CMVIG were both associated with significantly (P≤0.05) lower rates of graft loss and death versus no prophylaxis. After adjustment, CMVIG was associated with a significantly decreased adjusted risk for graft loss and a borderline (P=0.09) decreased adjusted mortality risk; antiviral prophylaxis was associated with decreased adjusted risk for graft loss and mortality. In the CMV-positive donor/CMV-negative recipient cohort, CMVIG (with or without antivirals) was associated with decreased adjusted risk for graft loss and death. CONCLUSIONS CMV prophylaxis with CMVIG or antivirals seems to offer long-term clinical outcome benefits. Determination of optimal regimen, dosage, and duration remains to be examined.